DESCRIPTION

Cytogam® , Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV), is an immunoglobulin G (IgG) containing a standardized amount of antibody to Cytomegalovirus (CMV). CMV-IGIV is formulated in final vial as a sterile liquid. The globulin is stabilized with 5% sucrose and 1% Albumin (Human). Cytogam® contains no preservative. The purified immunoglobulin is derived from pooled adult human plasma selected for high titers of antibody for Cytomegalovirus (CMV) (1). Source material for fractionation may be obtained from another U.S. licensed manufacturer. Pooled plasma was fractionated by ethanol precipitation of the proteins according to Cohn Methods 6 and 9, modified to yield a product suitable for intravenous administration. A widely utilized solvent-detergent viral inactivation process is also used (2). Certain manufacturing operations may be performed by other firms. Each milliliter contains: 50 ± 10 mg of immunoglobulin, primarily IgG, and trace amounts of IgA and IgM; 50 mg of sucrose; 10 mg of Albumin (Human). The sodium content is 20-30 mEq per liter, i.e., 0.4-0.6 mEq per 20 mL or 1.0-1.5 mEq per 50 mL The solution should appear colorless and translucent.

INDICATIONS

Cytomegalovirus Immune Globulin Intravenous (Human) is indicated for the prophylaxis of
cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas and heart. In
transplants of these organs other than kidney from CMV seropositive donors into seronegative
recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.

DOSAGE AND ADMINISTRATION

The maximum recommended total dosage per infusion is 150 mg Ig/kg, administered according to the
following schedule:

Type of Transplant

Kidney

Liver, Pancreas, Lung, Heart

Within 72 hours of transplant:

150 mg/kg

150 mg/kg

2 weeks post transplant:

100 mg/kg

150 mg/kg

4 weeks post transplant:

100 mg/kg

150 mg/kg

6 weeks post transplant:

100 mg/kg

150 mg/kg

8 weeks post transplant:

100 mg/kg

150 mg/kg

12 weeks post transplant:

50 mg/kg

100 mg/kg

16 weeks post transplant:

50 mg/kg

100 mg/kg

Preparation For Administration

Remove the tab portion of the vial cap and clean the rubber stopper with 70% alcohol or equivalent. DO
NOT SHAKE VIAL; AVOID FOAMING.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Infuse the solution only if it is colorless, free of
particulate matter and not turbid.

Infusion

Infusion should begin within 6 hours after entering the vial and should be complete within 12 hours of
entering the vial. Vital signs should be taken preinfusion, mid-way and post-infusion as well as before
any rate increase. CYTOGAM should be administered through an intravenous line using an
administration set that contains an in-line filter (pore size 15µ) and a constant infusion pump (i.e., IVAC
pump or equivalent). A smaller in-line filter (0.2µ) is also acceptable. Pre-dilution of CYTOGAM
before infusion is not recommended. CYTOGAM should be administered through a separate
intravenous line. If this is not possible, CYTOGAM may be "piggybacked" into a pre-existing line if
that line contains either Sodium Chloride Injection, USP, or one of the following dextrose solutions
(with or without NaCl added): 2.5% dextrose in water, 5% dextrose in water, 10% dextrose in water,
20% dextrose in water. If a pre-existing line must be used, the CYTOGAM should not be diluted more
than 1:2 with any of the above-named solutions. Admixtures of CYTOGAM with any other solutions
have not been evaluated.

Initial Dose

Administer intravenously at 15 mg Ig per kg body weight per hour. If no adverse reactions occur after
30 minutes, the rate may be increased to 30 mg Ig/kg/hr; if no adverse reactions occur after a subsequent
30 minutes, then the infusion may be increased to 60 mg Ig/kg/hr (volume not to exceed 75 mL/hour).
DO NOT EXCEED THIS RATE OF ADMINISTRATION. The patient should be monitored closely
during and after each rate change.

Subsequent Doses

Administer at 15 mg Ig/kg/hr for 15 minutes. If no adverse reactions occur, increase to 30 mg Ig/kg/hr
for 15 minutes and then increase to a maximum rate of 60 mg Ig/kg/hr (volume not to exceed 75
mL/hour). DO NOT EXCEED THIS RATE OF ADMINISTRATION. The patient should be monitored
closely during each rate change.

CYTOGAM should be used with caution in patients with pre-existing renal insufficiency and in patients
judged to be at increased risk of developing renal insufficiency (including, but not limited to those with
diabetes mellitus, age greater than 65, volume depletion, paraproteinemia, sepsis and patients receiving
known nephrotoxic drugs). In these cases especially, it is important to assure that patients are not volume
depleted prior to CYTOGAM infusion. While most cases of renal insufficiency have occurred in
patients receiving total doses of 350 mg Ig/kg or greater, no prospective data are presently available to
identify a maximum safe dose, concentration or rate of infusion in patients determined to be at increased
risk of acute renal failure. In the absence of prospective data, recommended doses should not be
exceeded and the concentration and infusion rate selected should be the minimum practicable.

Potential adverse reactions are: flushing, chills, muscle cramps, back pain, fever, nausea, vomiting,
wheezing, drop in blood pressure. Minor adverse reactions have been infusion rate related – if the
patient develops a minor side effect (i.e., nausea, back pain, flushing), slow the rate or temporarily
interrupt the infusion. If anaphylaxis or drop in blood pressure occurs, discontinue infusion and use
antidote such as diphenhydramine and adrenalin.

To prevent the transmission of hepatitis viruses or other infectious agents from one person to another,
sterile disposable syringes and needles should be used. The syringes and needles should not be reused.

HOW SUPPLIED

CYTOGAM is supplied in a 50 mL single-dose vial (50 mg/mL).

The product presentation includes a package insert and the following component:

Presentation

Carton NDC
Number

Component

2.5 g

44206-532-11

CYTOGAM in a single-use vial [NDC 44206-532-90]

Storage

CYTOGAM should be stored between 2-8°C (36-46°F), and used within 6 hours after entering the vial.

Manufactured by: CSL Behring AG Bern, Switzerland. Revised: May 2018.

Side Effects

SIDE EFFECTS

Minor reactions such as flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, arthralgia,
and wheezing were the most frequent adverse reactions observed during the clinical trials of
CYTOGAM, Cytomegalovirus Immune Globulin Intravenous (Human). The incidence of these reactions
during the clinical trials was less than 6.0% of all infusions and such reactions were most often related
to infusion rates. A decrease in blood pressure was observed in 1 of 1039 infusions in clinical trials of
CYTOGAM. If a patient develops a minor side effect, slow the rate immediately or temporarily interrupt
the infusion.

Severe reactions such as angioneurotic edema and anaphylactic shock, although not observed during
clinical trials, are a possibility. Clinical anaphylaxis may occur even when the patient is not known to be
sensitized to immune globulin products. A reaction may be related to the rate of infusion; therefore,
carefully adhere to the infusion rates as outlined under DOSAGE AND ADMINISTRATION. If
anaphylaxis or drop in blood pressure occurs, discontinue infusion and use antidote such as
diphenhydramine and adrenalin.

Postmarketing

The following adverse reactions have been identified and reported during the post-approval use of
IGIV products:38

Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of
uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a
causal relationship to exposure to the product. Such is also the case with literature reports authored
independently.

Drug Interactions

DRUG INTERACTIONS

Antibodies present in immune globulin preparations may interfere with the immune response to live
virus vaccines such as measles, mumps, and rubella; therefore, vaccination with live virus vaccines
should be deferred until approximately three months after administration of CYTOGAM. If such
vaccinations were given shortly after CYTOGAM, a revaccination may be necessary. Admixtures of
CYTOGAM with other drugs have not been evaluated. It is recommended that CYTOGAM be
administered separately from other drugs or medications which the patient may be receiving (see DOSAGE AND ADMINISTRATION section).

WARNINGS

Because CMV-IGIV is made from human blood, it may carry a risk of transmitting infectious agents,
e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-
Jakob disease (CJD) agent. The risk of transmission of recognized blood-borne viruses is considered
to be low because of the viral inactivation and removal properties in the Cohn-Oncley cold ethanol
precipitation procedure used for purification of immune globulin products.13-15 Until 1993, cold
ethanol manufactured immune globulins licensed in the United States had not been documented to
transmit any viral agent. However, during a brief period in late 1993 to early 1994, intravenous immune
globulin made by one U.S. manufacturer was associated with transmission of Hepatitis C virus.16 To
further guard against possible transmission of blood-borne viruses, including Hepatitis C, CMV-IGIV
is treated with a solvent detergent viral inactivation procedure2 known to inactivate a wide spectrum of
lipid enveloped viruses, including HIV-1, HIV-2, Hepatitis B, and Hepatitis C.17 However, because
new blood-borne viruses may yet emerge, some of which may not be inactivated by the manufacturing
process or by solvent detergent treatment, CMV-IGIV, like any other blood product, should be given
only if a benefit is expected.

Immune Globulin Intravenous (Human) products have been reported to be associated with renal
dysfunction, acute renal failure, osmotic nephrosis and death.18-25 Patients predisposed to acute renal
failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age
greater than 65, volume depletion, sepsis, paraproteinemia or patients receiving known nephrotoxic
drugs. Especially in such patients, IGIV products should be administered at the minimum concentrations
available and the minimum rate of infusion practicable. While these reports of renal dysfunction and
acute renal failure have been associated with the use of many IGIV products, those containing sucrose
as a stabilizer (and given at daily doses of 350 mg/kg or greater) account for a disproportionate share of
the total number.18 CYTOGAM contains sucrose as a stabilizer. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal
failure.

During administration, the patient's vital signs should be monitored continuously and careful observation
made for any symptoms throughout the infusion. Epinephrine should be available for the treatment of an
acute anaphylactic reaction (see PRECAUTIONS section).

Precautions

PRECAUTIONS

General

CYTOGAM does not contain a preservative. The vial should be entered only once for administration
purposes and the infusion should begin within 6 hours. The infusion schedule should be adhered to
closely (see DOSAGE AND ADMINISTRATION: Infusion section). Do not use if the solution is turbid.

Although systemic allergic reactions are rare (see ADVERSE REACTIONS section), epinephrine and
diphenhydramine should be available for treatment of acute allergic symptoms. If hypotension or
anaphylaxis occur, the administration of the immunoglobulin should be discontinued immediately and an
antidote should be given as noted above.

Renal Function

Assure that patients are not volume depleted prior to the initiation of IGIV. Periodic monitoring of renal
function tests and urine output is particularly important in patients judged to have a potential increased
risk for developing acute renal failure. Renal function, including the measurement of blood urea
nitrogen (BUN) and serum creatinine should be assessed prior to the initial infusion of CYTOGAM and
again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product
should be considered. The recommended rate of CYTOGAM infusion for prophylaxis of CMV disease
in solid organ transplant patients is 60 mg Ig/kg/hr (see DOSAGE AND ADMINISTRATION).

Aseptic Meningitis Syndrome

An asepticmeningitis syndrome (AMS) has been reported to occur infrequently in association with
Immune Globulin Intravenous (Human) (IGIV) treatment.26-29 The syndrome usually begins within
several hours to two days following IGIV treatment. It is characterized by symptoms and signs including
severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea
and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several
thousand cells per cu.mm., predominantly from the granulocytic series, and elevated protein levels up to
several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough
neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may
occur more frequently in association with high dose (2 g/kg) IGIV treatment. Discontinuation of IGIV
treatment has resulted in remission of AMS within several days without sequelae.

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury
(TRALI)] in patients administered IGIV.34 TRALI is characterized by severe respiratory distress,
pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6
hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate
ventilatory support.

IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected,
appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product
and patient serum (see PRECAUTIONS: Laboratory Tests).

Thrombotic Events

Thrombotic events have been reported in association with IGIV35-37 (see ADVERSE REACTIONS).
Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors,
advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks
and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom
IGIV administration is being considered. Baseline assessment of blood viscosity should be considered
in patients at risk for hyperviscosity, including those with cryoglobulins, fasting
chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS: Laboratory Tests).

Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory
laboratory testing should be done (see PRECAUTIONS).

If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil
antibodies in both the product and the patient serum (see PRECAUTIONS).

Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should
be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting
chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS).

Pregnancy

Animal reproduction studies have not been conducted with Cytomegalovirus Immune Globulin
Intravenous (Human). It is also not known whether Cytomegalovirus Immune Globulin Intravenous
(Human) can cause fetal harm when administered to a pregnant woman or can affect reproduction
capacity. Cytomegalovirus Immune Globulin Intravenous (Human) should be given to a pregnant woman
only if clearly needed.

OVERDOSE

Although few data are available, clinical experience with other immunoglobulin preparations suggests
that the major manifestations would be those related to volume overload.

CONTRAINDICATIONS

CYTOGAM should not be used in individuals with a history of a prior severe reaction associated with
the administration of this or other human immunoglobulin preparations. Persons with selective
immunoglobulin A deficiency have the potential for developing antibodies to immunoglobulin A and
could have anaphylactic reactions to subsequent administration of blood products that contain
immunoglobulin A, including CYTOGAM.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

CYTOGAM contains IgG antibodies representative of the large number of normal persons who
contributed to the plasma pools from which the product was derived. The globulin contains a relatively
high concentration of antibodies directed against Cytomegalovirus (CMV). In the case of persons who
may be exposed to CMV, CYTOGAM can raise the relevant antibodies to levels sufficient to attenuate
or reduce the incidence of serious CMV disease.

Clinical Studies

Clinical studies have shown a 50% reduction in primary CMV disease in renal transplant patients given
CMV-IGIV3 and a 56% reduction in serious CMV disease4 in liver transplant patients given CMVIGIV.
CMV-IGIV prophylaxis was associated with increased survival in liver transplant recipients.5

In two separate clinical trials, CYTOGAM was shown to provide effective prophylaxis in renal
transplant recipients at risk for primary CMV disease. In the first randomized trial,3 the incidence of
virologically confirmed CMV-associated syndromes was reduced from 60% in controls (n=35) to 21%
in recipients of CMV immune globulin (n=24) (P <0.01); marked leukopenia was reduced from 37% in
controls to 4% in globulin recipients (P <0.01); and fungal or parasitic superinfections were not seen in
globulin recipients but occurred in 20% of controls (P=0.05). Serious CMV disease was reduced from
46% to 13%. There was a concomitant but not statistically significant reduction in the incidence of
CMV pneumonia (17% of controls as compared with 4% of globulin recipients). There was no effect
on rates of viral isolation or seroconversion although the rate of viremia was less in CYTOGAM
recipients. In a subsequent non-randomized trial in renal transplant recipients (n=36),6 the incidence of
virologically confirmed CMV-associated syndrome was reduced to 36% in the globulin recipients in
comparison to a 60% incidence in control patients (n=35) in the randomized trial. The rates of serious
CMV disease, and concomitant fungal and parasitic superinfection were similar to patients receiving
CMV-IGIV in the first trial.

In a randomized, double-blind, placebo-controlled trial in liver transplant recipients,4 the incidence of
serious CMV-associated disease was reduced from 26% in the 72 control patients to 12% in the 69
CMV-IGIV recipients (p=0.02); serious CMV-associated disease included CMV disease in 2 or more
organs, CMV pneumonia, or CMV-associated invasive fungal infection, the incidence of which was
18% in controls and 7% in CMV-IGIV recipients (p=0.04). In follow-up5 of the liver transplant patients
studied in this randomized controlled trial and a subsequent open-label trial,7 the one year survival of
the 72 control patients was 72% versus 86% in the 90 recipients of CMV-IGIV (p=0.03). In the
randomized control trial, the reduction in serious CMV-associated disease in CMV seronegative
recipients of livers from a CMV seropositive donor (7/19 in the CMV-IGIV group vs. 9/19 in control)
was less than in transplants with other donor and recipient serologic status (1/50 in the CMV-IGIV
group vs. 10/53 in the control group). This finding was similar to that of Merigan et al.8 in a study of
ganciclovir prophylaxis after heart transplantation. In this study, patients received ganciclovir IV at 5
mg/kg twice a day for the initial 14 days post-transplant, then at 6 mg/kg each day for 5 days per week
through day 28.

Recent studies of combined prophylaxis with CMV-IGIV and ganciclovir have shown reductions in the
incidence of serious CMV associated disease in CMV seronegative recipients of CMV seropositive
organs below that expected from one drug alone.9-12

Ham et al.9 used CMV-IGIV with a dosage schedule of 150 mg/kg CMV-IGIV within 72 hours of
transplant; 100 mg/kg at two, four, six and eight weeks following liver transplant and then 50 mg/kg at 12
and 16 weeks post-transplant in combination with ganciclovir (10 mg/kg/day for 14 days). The incidence
of CMV disease was reduced from an expected 60-80% rate to 7% in 15 seronegative recipients of a
seropositive organ.

Snydman10 using the CMV-IGIV dosage schedule listed under DOSAGE AND ADMINISTRATION
section in combination with ganciclovir (10 mg/kg/day for 14 days) reduced the incidence of serious
CMV disease in D+R- liver transplant recipients receiving placebo or one drug from 16/47 (34%) to
3/41 (7%) in patients receiving both drugs for prophylaxis.

Martin11 using CMV-IGIV 100 mg/kg every two weeks for six weeks followed by 50 mg/kg every two
weeks with a final dose at week 16, in combination with ganciclovir 10 mg/kg/day for 14 days after
transplantation, observed severe CMV disease in 1/74 (1%) of CMV seronegative recipients of a kidney
from a CMV seropositive donor, in 0/14 (0%) of CMV seronegative recipients of a kidney-pancreas
transplant from a CMV seropositive donor and in 1/12 (8%) of CMV seronegative recipients of a liver
from a CMV seropositive donor. The incidence of serious CMV disease with combined CMV-IGIV
and ganciclovir prophylaxis was lower than previous experience with single drug prophylaxis.

Valantine and Luikart12 compared prophylaxis with CMV-IGIV (biweekly for three months) in
combination with ganciclovir prophylaxis (IV at 5 mg/kg twice a day for the initial 14 days posttransplant,
then at 6 mg/kg through day 28) in 16 CMV seronegative recipients of hearts from CMV
seropositive donors with 16 matched controls receiving ganciclovir alone. The actuarial incidence of
CMV disease was reduced from 55% in the ganciclovir group to 46% in the combined group (p ≤0.06)
and survival was increased from 61% to 94% (p ≤0.001). In heart-lung or lung transplant patients in
whom either the donor or recipient was CMV seropositive, the actuarial incidence of CMV disease in
patients receiving ganciclovir alone (n=25) was 85% as compared to 36% of the 33 patients receiving
both CMV-IGIV and ganciclovir (p ≤0.05). Survival was 60% in the ganciclovir group and 80% in
patients receiving CMV-IGIV and ganciclovir (p ≤0.01).

PATIENT INFORMATION

Patients should be instructed to report all infections directly to their physician and to CSL Behring
Pharmacovigilance at 1-866-915-6958. The risks and benefits of this product should be discussed with
the patient. In addition, patients should be instructed to immediately report symptoms of decreased urine
output, sudden weight gain, and/or shortness of breath (which may suggest kidney damage) to their
physician.